DESCRIPTION: The proposed research is a multidisciplinary, multicenter, collaborative study to continue the investigation of the clinical, cardiac and genetic aspects of the LQTS, a heritable channelopathy with delayed repolarization, episodic malignant arrhythmias with syncope and sudden death. Three recently-identified ionic channel gene mutations have been shown to be responsible for the disordered ventricular repolarization in three forms of LQTS. The five year research plan consists of: 1) expansion of pedigrees involving 701 LQTS families and 4,277 family members already enrolled in an international registry; 2) identification of new LQTS gene mutations and expansion of the number of gene-identified affected and unaffected members in LQTS families with known gene mutations, using molecular genetic techniques; and 3) investigation of phenotype-genotype relationships in 200 genotyped families involving 1200 affected and unaffected family members regarding the clinical course of LQTS, T-wave repolarization phenomena, triggering factors for cardiac events, and co-morbidity associations, all by genotype. Functionally, the project will have five components: 1) a clinical component with four centers; 2) a genotype component involving two molecular genetic laboratories; 3) a statistical genetic component to investigate modifier genes; 4) a biostatistical component that will provide expertise in study design and statistical data analysis; and 5) a central coordination and data center. This integrated research program is intended to: 1) improve the presymptomatic diagnosis and treatment of LQTS; and 2) provide a fundamental understanding of the molecular basis of repolarization-related cardiac arrhythmias.